Therapeutics for dementia and Alzheimer's disease: New directions for precision medicine.

LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?

In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia.

Lithium suppression of tau induces brain iron accumulation and neurodegeneration.

Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer's disease), and may explain lithium-associated motor symptoms in susceptible patients.

Amine oxidase activity of ß-amyloid precursor protein modulates systemic and local catecholamine levels.

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of ß-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

Mitochondria in aging and Alzheimer's disease.

Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-beta peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-beta rich neuritic plaques of the Alzheimer's disease brain are a histopathological hallmark of the disease. Since its identification as a major constituent of neuritic plaques amyloid-beta has attracted intense research focus as the primary causative agent in the development of Alzheimer's disease. As a result, numerous reports now exist to propose potential neurotoxic mechanisms mediated by amyloid-beta. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid-beta in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-beta is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid-beta. Functional decline of mitochondria with aging is well established, and growing evidence attributes this decline to loss of mitochondrial DNA integrity in postmitotic cells including neurons. Oxidative stress due to mitochondrial failure may drive increased amyloidogenic processing of the amyloid-beta precursor protein, contributing to a loss of amyloid-beta precursor protein functionality and increased amyloid-beta production. Importantly, recent data show that amyloid-beta accumulates within mitochondria of the Alzheimer's disease brain. We speculate that age-related somatic mutation of mitochondrial DNA may be an important factor underlying sporadic Alzheimer's disease.

Calcium moderation of cadmium stress explored using a stress-inducible transgenic strain of Caenorhabditis elegans.

In a transgenic strain of Caenorhabditis elegans carrying a stress-inducible lacZ reporter gene, short-term sublethal exposure to heavy metals activates transgene expression. The transgene response to Cd2+ is strongly inhibited by Ca2+ ions; furthermore, Ca2+ reduces the net accumulation of Cd2+ by worms. Both Ca2+ and a variety of calcium uptake inhibitors (nifedipine, La3+, verapamil) depress the dose response of the transgene to Cd2+. Calcium ionophore (A23187) slightly increases transgene activity in control and Cd2+ treated worms, but has a much larger effect in the case of Mn2+, reflecting its much greater affinity for this ion.